A hydrophilic skeleton fluorinated polymer and its preparation method and application

Abstract

The present invention discloses a hydrophilic skeleton fluorine-containing polymer and its preparation method and application, belonging to the technical field of application-based material preparation. The hydrophilic skeleton fluorine-containing polymer of the present invention has a double hydrophilic structure of the skeleton and the side chain. Its good hydrophilicity enables it to have an excellent fluorine signal in the deep tissue of the organism, satisfying 19 The invention utilizes the characteristic of allyl (2-oxotetrahydrothiophene-3-yl) carbamate having dual reaction sites, introduces fluorine-containing 2-((2,2,2-trifluoroethyl)thio)ethane-1-amine into the system through a ring-opening reaction between an amino group and a thiolactone, obtains a precursor having dual reaction sites of a thiol group and a double bond, initiates photopolymerization with benzoin dimethyl ether, then introduces a carboxyl group at the end through thioglycolic acid, and finally obtains a fluorine-containing polymer with a dual hydrophilic skeleton and side chains through oxidation. The experimental operation is simple and the raw materials are readily available.

Description

Technical Field

[0001] The present invention belongs to application type fluorine-containing polymer 19 The technical field of preparation of F MRI probes particularly relates to a fluorine-containing polymer with dual hydrophilicity in the backbone and side chains and a preparation method thereof. Background Art

[0002] Magnetic resonance imaging is a molecular imaging diagnostic technology that is non-ionizing radiation, non-invasive, has high spatial resolution, and deep imaging penetration. However, a large number of water molecules in the human body are hydrogen MRI ( 1 While HMRI provides rich information, it also gives it a strong background signal, which can easily lead to "false positive" or "false negative" diagnostic results. The accurate diagnosis of hydrogen magnetic resonance imaging places high demands on the experience and diagnostic technology of clinicians. 19 F MRI) in the retained 1 In addition to the advantages of HMRI, it has the advantage of zero background noise, which is conducive to quantification and tracing, and provides more pathological details for disease diagnosis. It has received widespread attention due to its above-mentioned characteristics.

[0003] However, 19 F MRI technology is still in its early stages of development and can be used 19 There are still few types of probes for F MRI, and most of them are perfluorinated compound probes. These probes tend to remain in the body for a long time, and their biosafety needs further research. Fluorinated polymer probes have the characteristics of good biocompatibility, easy removal and modification, and have great potential. 19 F MRI has great potential for application. However, the preparation of fluorinated polymer probes still needs to overcome a series of difficulties: first, how to increase the content of equivalent fluorine atoms; second, how to improve the mobility of fluorine atoms in water to obtain good relaxation properties and thus enhance their signal intensity.

[0004] Therefore, it is necessary to develop a magnetic equivalent fluorine with high content, high relaxation performance and excellent 19 F MRI signal and biocompatibility 19 F MRI polymer probes are of great significance. Summary of the Invention

[0005] based on 19 In order to meet the needs of F MRI probe development, the present invention aims to provide a hydrophilic backbone fluoropolymer and its preparation method and application. The hydrophilic backbone fluoropolymer of the present invention is a fluoropolymer with dual hydrophilicity in the backbone and side chains, and has excellent 19 F MRI signal, which has the potential for deep tissue imaging.

[0006] The present invention is achieved in that:

[0007] The present invention first provides a hydrophilic skeleton fluorine-containing polymer,

[0008] It has the following chemical structure:

[0009]

[0010] However, n is 5-20, and more preferably 8-10.

[0011] The present invention also provides a method for preparing the hydrophilic skeleton fluorinated polymer, and its synthesis route is as follows:

[0012]

[0013] The synthesis steps are as follows:

[0014] Step 1: performing a ring-opening reaction on allyl (2-oxotetrahydrothiophen-3-yl) carbamate using 2-((2,2,2-trifluoroethyl)thio)ethane-1-amine, and initiating a photopolymerization reaction using benzoin dimethyl ether to obtain polymer 1;

[0015] Step 2: introducing a carboxyl group at the end of polymer 1 by using thioglycolic acid to obtain polymer 2;

[0016] Step 3: oxidize polymer 2 to obtain a hydrophilic skeleton fluorine-containing polymer.

[0017] Specifically, step 1 is: weighing an appropriate amount of allyl (2-oxotetrahydrothiophene-3-yl) carbamate into a reaction vessel, dissolving it with an organic solvent, then passing nitrogen into the reaction vessel, adding 4-dimethylaminopyridine and benzoin dimethyl ether to the reaction vessel, adding 2-((2,2,2-trifluoroethyl)thio)ethane-1-amine under light-proof conditions, keeping the reaction device sealed, reacting under light-proof conditions, and then reacting under 365nm light conditions to obtain polymer 1.

[0018] Specifically, in step 1, the reaction time is 0.5 h to 1 h under light-proof conditions, and the reaction time is 5 h to 15 h under 365 nm light irradiation conditions.

[0019] Specifically, in step 1, the molar ratio of the added allyl(2-oxotetrahydrothiophen-3-yl)carbamate to 2-((2,2,2-trifluoroethyl)thio)ethane-1-amine is 0.5-1.

[0020] Specifically, in steps 1 and 2, the organic solvent used in the reaction system is 1,4-dioxane.

[0021] Specifically, in step 2, the molar ratio of the added thioglycolic acid to the polymer 1 is 1 to 2.

[0022] Specifically, in step 3, hydrogen peroxide is used to oxidize the polymer 2.

[0023] The present invention also provides the hydrophilic skeleton fluorine-containing polymer or the hydrophilic skeleton fluorine-containing polymer prepared by the above method as 19 Application of F magnetic resonance imaging contrast agents.

[0024] Beneficial effects of the present invention:

[0025] The fluorine-containing polymer of the present invention has a double hydrophilic structure of the skeleton and the side chain and has excellent 19 F MRI signals have the potential for deep tissue imaging. The present invention's method for preparing a hydrophilic backbone fluoropolymer utilizes the dual-reactive site property of allyl (2-oxotetrahydrothiophen-3-yl) carbamate. Fluorine-containing 2-((2,2,2-trifluoroethyl)thio)ethane-1-amine is introduced into the system via a ring-opening reaction between the amino group and thiolactone, yielding a precursor with dual reactive sites of thiol and double bonds. Photopolymerization is then initiated using benzoin dimethyl ether, followed by the introduction of carboxyl groups at the termini using thioglycolic acid. Finally, oxidation is performed to yield a hydrophilic backbone fluoropolymer with dual hydrophilicity in both the backbone and side chains. The experimental procedure is simple and the raw materials are readily available. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is the NMR spectrum of polymer 1 prepared in Example 1;

[0027] Figure 2 This is the NMR spectrum of polymer 2 prepared in Example 4;

[0028] Figure 3 This is the NMR spectrum of polymer 3 prepared in Example 5;

[0029] Figure 4 This is a relaxation performance diagram of polymer 3 prepared in Example 5;

[0030] Figure 5 In vivo performance of polymer 3 prepared in Example 5 19 F MRI performance characterization diagram. DETAILED DESCRIPTION

[0031] In order to better explain the present invention, the present invention will be described in detail with reference to the embodiments of the present invention, and the main contents of the present invention will be further illustrated in conjunction with specific examples, but the content of the present invention is not limited to the following examples. Where specific techniques or conditions are not specified in the examples, the techniques or conditions described in the literature in this area or the product specifications are used. Where the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be obtained commercially.

[0032] The invention uses allyl (2-oxotetrahydrothiophene-3-yl) carbamate as a starting material. First, allyl (2-oxotetrahydrothiophene-3-yl) carbamate, 2-((2,2,2-trifluoroethyl)thio)ethane-1-amine, benzoin dimethyl ether, and 4-dimethylaminopyridine are dissolved in 1,4-dioxane, and a polymerization reaction is carried out under nitrogen protection and light with a wavelength of 365 nm to form polymer 1. Subsequently, thioglycolic acid is added to the reaction system to continue the reaction. After the reaction is completed, precipitation is carried out with methyl tert-butyl ether, redissolution is carried out in tetrahydrofuran, and precipitation with methyl tert-butyl ether is repeated three or more times. The polymer is dried at room temperature to obtain fluorine-containing polymer 2. Finally, hydrophobic sulfide is oxidized to a hydrophilic sulfoxide structure with hydrogen peroxide to obtain polymer 3, which is a hydrophilic skeleton fluorine-containing polymer.

[0033] The chemical structure of polymer 1 is

[0034] The chemical structure of polymer 2 is

[0035] The chemical structure of polymer 3 is

[0036] The fluorine-containing polymer and its preparation method of the present invention are described in more detail below through examples and performance tests. However, the embodiments of the present invention are not limited to the following examples.

[0037] Example 1 Synthesis of Polymer 1

[0038] First, allyl (2-oxotetrahydrothiophene-3-yl) carbamate (402.0 mg, 2.0 mmol) was weighed into a quartz tube and dissolved with 1 mL of 1,4-dioxane. Then, nitrogen was passed through the reaction vessel for 30 min. 4-Dimethylaminopyridine (70.0 mg) and benzoin dimethyl ether (25.0 mg) were then added to the reaction vessel. 2-((2,2,2-trifluoroethyl)thio)ethane-1-amine (640.0 mg, 4.0 mmol) was added under light-proof conditions. Nitrogen was continued to be passed through for 5 min and the reaction device was sealed. The reaction was allowed to react for 1 h under light-proof conditions and then reacted under 365 nm illumination conditions for 5 h. After the reaction was completed, the product was precipitated with methyl tert-butyl ether, dissolved in tetrahydrofuran, and then precipitated with methyl tert-butyl ether. This was repeated three times and dried at room temperature to obtain polymer 1 (yield 81.4%, M n,SEC =2218, DP=9), NMR spectrum as shown Figure 1 shown.

[0039] Example 2 Synthesis of Polymer 1

[0040] First, allyl (2-oxotetrahydrothiophene-3-yl) carbamate (402.0 mg, 2.0 mmol) was weighed into a quartz tube and dissolved with 1 mL of 1,4-dioxane. Then, nitrogen was passed through the reaction vessel for 30 min. 4-Dimethylaminopyridine (70.0 mg) and benzoin dimethyl ether (25.0 mg) were then added to the reaction vessel. 2-((2,2,2-trifluoroethyl)thio)ethane-1-amine (640.0 mg, 4.0 mmol) was added under light-proof conditions. Nitrogen was continued to be passed through for 5 min and the reaction device was sealed. The reaction was allowed to react for 1 h under light-proof conditions and then for 10 h under 365 nm illumination conditions. After the reaction was completed, the product was precipitated with methyl tert-butyl ether, dissolved in tetrahydrofuran, and then precipitated with methyl tert-butyl ether. This was repeated three times and dried at room temperature to obtain polymer 1 (yield 81.4%, M n，SEC =1983,DP=9).

[0041] Example 3 Synthesis of Polymer 1

[0042] First, allyl (2-oxotetrahydrothiophene-3-yl) carbamate (402.0 mg, 2.0 mmol) was weighed into a quartz tube and dissolved with 1 mL of 1,4-dioxane. Then, nitrogen was passed through the reaction vessel for 30 min. 4-Dimethylaminopyridine (70.0 mg) and benzoin dimethyl ether (25.0 mg) were then added to the reaction vessel. 2-((2,2,2-trifluoroethyl)thio)ethane-1-amine (640.0 mg, 4.0 mmol) was added under light-proof conditions. Nitrogen was continued to be passed through for 5 min and the reaction device was sealed. The reaction was allowed to react for 1 h under light-proof conditions and then reacted under 365 nm illumination conditions for 15 h. After the reaction was completed, the product was precipitated with methyl tert-butyl ether, dissolved in tetrahydrofuran, and then precipitated with methyl tert-butyl ether. This was repeated three times and dried at room temperature to obtain polymer 1 (yield 81.4%, M n，SEC =1904, DP=9).

[0043] Example 4 Synthesis of Polymer 2

[0044] The polymer 1 (361.0 mg, repeating unit molar weight 1.0 mmol) prepared in Example 1 was weighed into a quartz tube, dissolved with 1 mL of 1,4-dioxane, and then nitrogen was passed into the reaction vessel for 30 minutes. Benzoin dimethyl ether (10.0 mg) was then added to the reaction vessel, and thioglycolic acid (92.0 mg, 1.0 mmol) was added. The nitrogen was continued to pass for 5 minutes and the reaction device was kept sealed. The reaction was then carried out at 365 nm for 2 hours. After the reaction was completed, methyl tert-butyl ether was used for precipitation, and after dissolving with tetrahydrofuran, methyl tert-butyl ether was continued for precipitation, and the reaction was repeated three times. The product was dried at room temperature to obtain polymer 2 (yield 85.1%). The nuclear magnetic spectrum is shown as follows: Figure 2shown.

[0045] Example 5 Synthesis of Polymer 3

[0046] Polymer 2 (361.0 mg, repeating unit molar weight 1.0 mmol) prepared in Example 4 was weighed into a 10 mL vial and dissolved in 2 mL of tetrahydrofuran. A 30% aqueous hydrogen peroxide solution (440.0 μL, 4.0 mmol) was then added and the mixture was allowed to react at 45°C for 48 h. After the reaction was complete, polymer 3 was obtained as a white solid (yield 80.3%) using methyl tert-butyl ether. The NMR spectrum is shown below. Figure 3 shown.

[0047] <Performance Test>

[0048] 1. Relaxation performance test of polymer 3

[0049] The instrument was a Bruker-400M nuclear magnetic resonance spectrometer; the T1 sequence was "tlir"; and the T2 sequence was "cpmg".

[0050] T2 main parameters: scan number NS: 4; empty scan number DS: 4; relaxation delay D1 = 10s; D 20 :0.002s.

[0051] T1 main parameters: NS=4; DS=4; D1=10s.

[0052] Sample preparation: Take polymer 3 (10 mg) prepared in Example 5, dissolve it in 0.5 mL of water, and place it in an NMR tube containing a heavy water capillary (for field lock). The default temperature is 298 K (modify to the desired temperature when testing at different temperatures). First, obtain a fluorine spectrum in the NMR spectrometer, and then perform T1 and T2 measurements. The T1 value can be directly simulated with Topspin software, and the T2 value is calculated using the formula:

[0053] T2=Fitting cycle number*(2D 20 +P2)…………………………Formula (2-1)

[0054] The relaxation performance test results of polymer 3 are as follows Figure 4 shown.

[0055] 2. In vivo application of polymer 3 19 F MRI performance characterization

[0056] The polymer 3 solution (150 mg / mL) prepared in Example 5 was injected into the tumor of mice (Babl / c, 4 to 5 weeks old, weighing 18 to 21 g) and the tumor was examined on a small animal MRI instrument. 19 FMRI testing.19 The F MRI test sequence was T2_RARE. The relevant parameters were as follows: MTX: 100×100, slice thickness (5 mm), FOV: 40 mm×40 mm, TE: 4.64 ms, TR: 3000 ms, and NS: 1.

[0057] In vivo polymer 3 19 F MRI performance characterization results are shown in Figure 5 shown.

[0058] pass Figure 4-5 The test results shown in the figure show that the hydrophilic skeleton fluorinated polymer prepared by the present invention has a hydrophilic sulfoxide structure in the skeleton and side chain, which can effectively maintain the mobility of fluorine atoms in water and has good relaxation properties, and can be used for deep tissues of organisms. 19 F MRI.

[0059] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. A hydrophilic backbone fluorine-containing polymer, characterized in that: It has the following chemical structure: Here, n is 5 to 20.

2. The hydrophilic skeleton fluorinated polymer according to claim 1, characterized in that n is 8 to 10.

3. A method for preparing the hydrophilic skeleton fluorinated polymer according to claim 1, characterized in that: The synthetic route is as follows: The synthesis steps are as follows: Step 1: performing a ring-opening reaction on allyl (2-oxotetrahydrothiophen-3-yl) carbamate using 2-((2,2,2-trifluoroethyl)thio)ethane-1-amine, and initiating a photopolymerization reaction using benzoin dimethyl ether to obtain polymer 1; Step 2: introducing a carboxyl group at the end of polymer 1 by using thioglycolic acid to obtain polymer 2; Step 3: oxidize polymer 2 to obtain a hydrophilic skeleton fluorine-containing polymer.

4. The method for preparing a hydrophilic skeleton fluorinated polymer according to claim 3, wherein: The step 1 specifically comprises: weighing an appropriate amount of allyl (2-oxotetrahydrothiophene-3-yl) carbamate into a reaction vessel, dissolving it with an organic solvent, then passing nitrogen into the reaction vessel, adding 4-dimethylaminopyridine and benzoin dimethyl ether into the reaction vessel, adding 2-((2,2,2-trifluoroethyl)thio)ethane-1-amine under light-proof conditions, keeping the reaction device sealed, reacting under light-proof conditions, and then reacting under 365 nm light conditions to obtain polymer 1.

5. The method for preparing a hydrophilic skeleton fluorinated polymer according to claim 4, wherein: In the step 1, the reaction time is 0.5 h to 1 h under light-proof conditions, and the reaction time is 5 h to 15 h under 365 nm light irradiation conditions.

6. The method for preparing a hydrophilic skeleton fluorinated polymer according to claim 4, wherein: In the step 1, the molar ratio of the added allyl(2-oxotetrahydrothiophen-3-yl)carbamate to 2-((2,2,2-trifluoroethyl)thio)ethane-1-amine is 0.5-1.

7. The method for preparing a hydrophilic skeleton fluorinated polymer according to claim 3, wherein: In steps 1 and 2, the organic solvent used in the reaction system is 1,4-dioxane or tetrahydrofuran.

8. The method for preparing a hydrophilic skeleton fluorinated polymer according to claim 3, wherein: In the step 2, the molar ratio of the added thioglycolic acid to the polymer 1 is 1 to 2.

9. The method for preparing a hydrophilic skeleton fluorinated polymer according to claim 3, wherein: In the step 3, hydrogen peroxide or m-chloroperbenzoic acid is used to oxidize the polymer 2.

10. The hydrophilic backbone fluorinated polymer according to any one of claims 1 to 2 or the hydrophilic backbone fluorinated polymer prepared by the method according to any one of claims 3 to 9 as 19 Application of F magnetic resonance imaging contrast agents.

Images